Molecular Regulation of the Mitochondrial F₁F_o-ATPsynthase: Physiological and Pathological Significance of the Inhibitory Factor 1 (IF ₁ )

Figure 1

Oxidative phosphorylation and the mammalian F₁F_o-ATPsynthase. (a) Scheme of the mitochondrial OXPHOS: it is composed of five complexes, which couple the generation of a proton motive force through the mitochondrial inner membrane (IMM) with ATP synthesis. The first four complexes form the electron-transport chain (ETC), which catalyses the oxidation of NADH and FADH₂ to NAD⁺ and FAD respectively, with the associated reduction of molecular oxygen, to which electrons are transferred, to water. During the process, protons are translocated against a gradient in the intermembrane space by complexes I, III, and IV; the generation of a proton electrochemical potential (Δ𝜇_𝐻+), also called proton motive force (pmf), is achieved, driving the ATP synthesis, which is catalyzed as the final step by the F₁F_o-ATP synthase (Complex V). The supramolecular organization of the respiratory chain, with the F₁F_o-ATPsynthase localized to mitochondrial cristae, where a higher surface density of protons is realized, allows a better enzymatic performance of complex V. (b) Diagram of the structure of mammalian F₁F_o-ATPsynthase. We can divide the enzymatic complex into 4 principal subdomains: a catalytic headpiece (𝛼₃𝛽₃), hosting the three catalytic sites for ATP synthesis (one in each 𝛽 subunit), a proton channel (𝑎𝑐₈) and two stalks, the central rotor (𝛾𝛿𝜀) and the peripheral stator (𝑏𝑑(F₆)OSCP) that link the first two subdomains together. While protons flow through the F_o channel from the intermembrane space into the matrix, a rotation of the stator inside the catalytic headpiece is induced, allowing a cyclic change in 𝛽-subunits conformation and the synthesis of ATP (N.B. Subunits A6L, 𝑒, 𝑓, and 𝑔 are omitted in the scheme).